Down syndrome (DS), occurs due to constitutional trisomy 21 and is associated with mental retardation, congenital structural defects as well as predisposition to leukemias. Children with DS are at a substantial risk of developing AML with a nearly 500 fold higher risk of AML than non-DS children. Further, transient myeloproliferative disorder (TMD) which is morphologically indistinguishable from AML is diagnosed in DS infants <3 months of age, with nearly 70% of cases with spontaneous resolution. AML diagnosed in DS is quite distinct from those in non DS patients with blasts showing megakaryocytic features (acute megakaryocytic leukemia; AMKL). Children with DS AML show exquisite sensitivity to cytotoxic therapies, with higher rates of toxicities and treatment related mortality (TRM) with conventional therapies, leading to suboptimal outcomes due to excess TRM. However, with more measured therapies, such sensitivities have led to improved outcome compared to their non-DS AML. Mutations in GATA1 gene and a few other candidate genes have been implicated in the pathogenesis of DS AML, but broader genomic studies in DS AML have lagged behind more prevalent types of leukemias with recent studies in childhood AML completing large cohort studies of de novo AML with very limited data in DS AML. Although outcomes in DS AML have improved in the last two decades, cytotoxic therapies continue to cause substantial short and long term toxicities in this very susceptible population. Comprehensive studies including whole genome (WGS) and transcriptome sequencing (RNA seq) can inform the underlying mechanism for malignant transformation and identify potential therapeutic targets for more precise therapeutic development. We propose to discover genomic and transcript variants that are uniquely associated with DSAML by conducting WGS and RNA seq in diagnostic and remission (germline) specimens from patients enrolled in the most recent COG DS-AML and DS-TMD studies. Of particular interest is the differences between TMD and AML to define the underlying genomic and functional/biologic variations that leads to spontaneous resolution in TMD. This exact patient cohort was originally included in our X01 application (Germline and Somatic Variants in Myeloid Malignancies in Children). Newly released INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndrome) aims to specifically study the co-occuring conditions in children with DS. As this patient population is within the scope of both X01 and INCLUDE projects, it provides a unique opportunity for the two projects to work together and synergize towards defining the underlying mechanism of myeloid pathogenesis in this unique cohort of vulnerable patients who can most benefit from less toxic therapies.